Capsaicin (But Not Other Vanillins) Enhances Estrogen Binding to Its Receptor: Implications for Power Sports and Cancers.

Capsaicin (CAP), the pain-inducing compound in chili peppers, exerts its effects mainly through the transient receptor potential vanilloid channel 1 (TRPV1), which mediates pain perception and some metabolic functions. CAP has also been demonstrated to improve performance in power sports (but not endurance sports) and does so mainly for females. CAP may also have anti-cancer effects. Many mechanisms have been explored to explain these phenomena, particularly the effects of TRPV1 activation for calcium influx, glucose transporter (GLUT) upregulation and inhibition of insulin (INS) production, but two important ones seem to have been missed. We demonstrate here that CAP binds to both INS and to the estrogen receptor (ESR1), enhancing estradiol binding. Other TRPV1 agonists, such as vanillin, vanillic acid and acetaminophen, have either no effect or inhibit estrogen binding. Notably, TRPV1, ESR1 and INS share significant regions of homology that may aid in identifying the CAP-binding site on the ESR1. Because activation of the estrogen receptor upregulates GLUT expression and thereby glucose transport, we propose that the observed enhancement of performance in power sports, particularly among women, may result, in part, from CAP enhancement of ESR1 function and prevent INS degradation. Chronic exposure to CAP, however, may result in downregulation and internalization of ESR1, as well as TRPV1 stimulation of glucagon-like peptide 1 (GLP-1) expression, both of which downregulate GLUT expression, thereby starving cancer cells of glucose. The binding of capsaicin to the ESR1 may also enhance ESR1 antagonists such as tamoxifen, benefiting some cancer patients.